Development, Validation and Successful Application of an In Vitro-In Vivo Correlation Model for Sustained Release Tablets of Bupropion Hydrochloride

摘要

Background: In vitro-in vivo correlation (IVIVC) is a quantitative and reliable relationship between in vitro drug release and in vivo absorption, which is desirable for rational development and optimization of sustained release formulations. The present work demonstrates developmentand application of IVIVC for 150 mg sustained release tablets of bupropion hydrochloride. Methods: Two sustained release prototype tablets of bupropion were formulated and optimal dissolution method was developed with USP type 2 (paddle type, with sinker) apparatus operated at 100 rpm,using 900 ml of phosphate buffer (pH 6.8). Prototypes were evaluated to obtain in vitro data for IVIVC model development. Primary in vivo dataset for development of IVIVC model was the individual plasma concentration data from two arms of a three-way crossover study in 15 healthy volunteerspost administration of the prototypes. The third arm was a reference formulation for external validation. Mean plasma concentration data of immediate release formulation from literature was used to compute the in vivo weighting function. Results: A deconvolution based approach was employedto generate in vivo input function (fraction drug absorbed). A linear correlation model was developed between fraction absorbed and fraction dissolved and was validated (internal and external) based on prediction error of pharmacokinetic parameters. The prediction errors were less than 10for both internal and external validations, demonstrating the validity of developed model. Conclusion: A ‘level A’ IVIVC was developed and validated for bupropion hydrochloride and the model was successfully applied to select a prototype for pivotal bioequivalence study.